The long-range objective of this project is to seek an understanding of the ecologica epidemiological behavior of arthropod-borne togaviruses by learning more about the viruses themselves and their interactions with cells of the two phyla -- arthropods and vertebrate -- which play a crucial role in their transmission cycle. In nature, effective transmission requies that the arthropod survive an infectious bloodmeal and retain normal biting capacity through the extrinsic incubation period (10-12 days) and beyond. Disease production in vertebrate hosts depends, at least in part, on the capacity of the viruses to cause cellular injury. The contrasting responses of the two kinds of hosts are mirrored in those of cell cultures derived from them, especially in alphavirus infections: both kinds of cells support virus replication, but cytopathic effects (CPE) typically occur in cell cultures of warmblooded vertebrate orgin, not in mosquito cell cultures. We shall study mechanisms involved in virus replication and in cellular injury by comparing Sindbis virus infection of CPE-susceptible and -resistant Aedes albopictus cell clones and of BHK21 and other vertebrate cells. Aspects of special interest are (1) macromolecular synthetic processes and their regulation, including characterization of RNA polymerases, (2) role of monovalent cation concentration, (3) cell species-specific effects in the generation of defective-interfering viral particles and/or genomes, (4) role of defectives and temperature-sensitive viral mutants in persistent infection, (5) differential effects of various metabolic inhibitors on the outcome of virus-cell interactions. The flaviviruses, the other major genus of arthropod-borne togaviruses, include many serious human pathogens. They differ in many basic characteristics from the alphaviruses, but much less is known about their structure, genetics, and molecular biology, We shall continue to examine several aspects of RNA structure, transcription, and translation of dengue virus. Based on the information obtained, we shall then proceed to comparative studies similar to those underway with alphaviruses.